Dna

FIGURE 5.36 Coordination complex generated from the cisplatin active species and DNA.

which deforms the DNA tertiary conformation as shown by X-ray crystallography and causes its unwinding at the complexation site (Fig. 5.36).59 As a consequence, high-mobility group (HMG) domain proteins become attached to DNA by intercalation of a phenylalanine unit at the unwound DNA damage site and the protein lies along a widened minor groove, preventing DNA replication.60 Although, strictly speaking, Pt coordination with DNA bases cannot be considered an alkylation reaction, cisplatin and its analogs are normally studied among the alkylating agents.

An additional mechanism for prevention of DNA transcription is replacement of Zn by Pt in the so-called zinc-finger protein transcription factor. The existence of the zinc cation is essential to coordinate amino acids of the protein, usually cysteine and histidine, and thus pack together the DNA binding domains into a dense structure. Replacing the zinc ion with platinum disrupts the conformation, and binds the zinc-finger permanently to DNA-polymerase a, which is a transcription enzyme vital for cell replication (Fig. 5.37). Pt-DNA adducts also activate several cellular processes that mediate the cytotoxicity of these anticancer drugs.61

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